Alzheimer's Disease (AD) is characterized by deterioration of intellectual and emotional functioning, afflicting 40% of those over 85. Pathological hallmarks of the disease include amyloid beta (AB) plaques and neurofibrillary tangles, which play a key role in the pathogenic mechanism of AD, evolving in a temporal and spatial manner. We are interested in understanding the early mechanisms that cause or perpetuate this temporal and spatial progression of AD pathogenesis. Recently, a triple transgenic (3xTg-AD) mouse model of AD that develops both amyloid and tau pathology has been created, which to date is the best model system depicting what occurs in human AD. We have found significant upregulation of TNF-a in this model prior to amyloid pathology and want to investigate the role of this cytokine in early disease. We hypothesize that TNF-a mediate inflammation perpetuates disease in an AD model where genetic predisposition to amyloid and tan pathologies exist and that dampening this inflammatory response will diminish the pathological amyloid and tau outcome. Additionally, we hypothesize that the focal induction of an inflammatory event prior to the onset of inflammation will exacerbate pathological outcomes in a regional and temporal manner. We will administer recombinant adeno-associated virus (rAAV) vectors expressing either TNF-a to create a sustained foe inflammatory response or a TNF receptor antagonist to inhibit the endogenous inflammatory response prior to existing pathology. This work will give us major insight on the involvement of inflammation in the temporal and spatial progression of early AD pathogenic events and may potentially provide a new therapeutic target.